Moisture is the nemesis of strong polymer adhesion to metals and minerals. Most engineered adhesive polymers require extensive prior surface cleaning, drying, and sometimes even chemical modification for effective adhesion to polar surfaces. Such surface preparation is difficult in vivo since biomineralized tissues and implant material surfaces are necessarily hydrated within the body. Various marine organisms have evolved highly effective adhesive strategies for wet surfaces. The broad goal of this proposal is to obtain mechanistic information about marine adhesion in order to translate it into effective applications for restoration and repair of hard tissues. While the discovery of 3,4-dihydroxyphenylalanine (Dopa)-protein involvement in adhesion has already inspired several new biomedical materials, Dopa is not the only bioinspired theme. The specific aims here are to determine using mass spectrometry whether and to what extent phosphoserine and 4-hydroxyarginine are linked to mussel adhesion on different surfaces, characterize the specific protein-protein interactions during adhesive cross-linking, and to explore how factors such as mass, primary sequence, and side- chain functionalization influence the coating or bridging behavior of mfp-1 on surfaces such as titanium and hydroxyapatite using the surface forces apparatus. Bio-inspired adhesives and sealants are much needed in dentistry and orthopedics not just to improve the strength and durability of bonding to hard tissues, but also to emancipate the present technology, particularly in dentistry, from a reliance on highly reactive and toxic organic formulations. PUBLIC HEALTH RELEVANCE: In dental and biomedical restorations, water is the nemesis of true adhesion between solid surfaces and polymers. The strong underwater adhesion of marine organisms such as mussels is based on an adaptive set of molecular and biophysical properties that will be systematically translated into medically relevant strategies.